1. Technical Field
The present invention relates generally to methods for treating human disease conditions associated with the human immunodeficiency virus (HIV) and more particularly to the use of monoclonal antibodies directed against anti-self cytotoxic T-lymphocytes or their lytics in order to inhibit or treat HIV and related HIV diseases.
2. Description of the Related Art
Several viruses produce latent infection in humans and can reactivate to produce recrudescent or persistent disease. One such disease is the human immunodeficiency virus (HIV). HIV is associated with a progressive catastrophic disease in certain primates, including humans. Humans infected with HIV experience proliferation of a certain class of white blood cells known as cytotoxic T-lymphocytes (CTL). The final stage of this disease is commonly known as acquired immune deficiency syndrome (AIDS).
It is well known in the art that the clinical signs and symptoms of AIDS are primarily due to a profound loss of all lymphocytes marked with the CD3 and CD4 antigens (CD4+ T-lymphocytes). It is also generally accepted that the infectious agent in AIDS is the human immunodeficiency virus (HIV). Although HIV infects and destroys CD4+ cells, the number of cells infected is inadequate to account for the profound and indiscriminate loss of these cells that occurs in individuals infected with HIV. It has been suggested by those in the field that autoimmunity may play a role in the pathogenesis of AIDS. However, few have suspected a pathogenic cytotoxic T-lymphocyte (CTL).
Rather, it is generally accepted by those skilled in the art that CTL""s are beneficial for those infected with HIV since it is believed CTL""s help control the infection, i.e., CTL""s are believed to be prognosticators that delay the progression of AIDS. Klimas, et al., xe2x80x9cPhase I Trial of Adoptive Therapy with Purified CD8 Cells in HIV Infectionxe2x80x9d, Int. Conf. AIDS, Jul. 19-24, 1992; Abstract No. PoB 3446, for example, have described infusion of CTL""s into the bloodstream of HIV-infected patients as an experimental method of treatment. This particular type of infusion was directed to the mitogen-expanded colonies of the host patient""s autologous CD8+ cells, a lymphocyte population that includes CTL""s.
However, Zarling, et al, xe2x80x9cHIV-Infected Humans, But Not Chimpanzees, Have Circulating Cytotoxic T-Lymphocytes That Lyse Uninfected CD4+ Cellsxe2x80x9d, J. Immunol. 1990; 144: 2992-98 have shown that HIV-infected humans have an anti-self, anti-CD4 CTL in their circulating blood that lyses healthy, uninfected CD4+ cells. No such CTL was found in the blood of HIV-seronegative humans. Moreover, no such CTL or suicide cell was found in the blood of HIV-infected chimpanzees. This is significant because HIV infection manifests as a nonpathogenic colonization in the blood and tissue of chimpanzees.
T cell-monocyte adhesion pathways are important in HIV replication. Diegel. et al, xe2x80x9cRegulation of HIV Production by Blood Mononuclear Cells from HIV Infected Donors: II. HIV-1 Production Depends on T Cell-Monocyte Interactionxe2x80x9d, AIDS Res. Hum. Retroviruses, 1993; 9:465-73 teach that blocking of either CD2-LFA-3 or CD18-ICAM-1 results in greater than 90% inhibition of HIV-1 production stimulated by anti-CD3 or staphylococcal enterotoxin/superantigen. Inhibition of HIV production, but not inhibition of CD4+ T lymphocyte proliferation, was observed when either the T cell or monocyte coreceptor was bound by monoclonal antibodies to these adhesion molecules. It is known that adhesion molecules are essential for an interaction between cytotoxic T lymphocytes (CTL) and their target cells. As mentioned above, Zarling, et al. have shown that HIV-infected humans, but not HIV-infected chimpanzees, have circulating CTL that lyse uninfected CD4+ T cells. Because HIV-infected chimpanzees do not develop HIV disease, autoreactive CTL directed against healthy CD4+ cells, and other adverse CTL effects, may account for the emergence of disease in HIV-infected humans.
The present invention envisions treatment of HIV infection by infusing a dose of monoclonal antibodies (MAbs) to inhibit overproduction of Lymphocyte function-associated molecule 1 (LFA-1) on CD8 cells. Monoclonal antibodies that inhibit overproduction of LFA-1 are referred to herein as xe2x80x9canti-LFA-1 MAbsxe2x80x9d. The LFA-1 adhesion molecule has an alpha (xcex1) chain and a beta (xcex2) chain. The a chain includes approximately 100 binding sites, as does the xcex2 chain. LFA-1xcex1 thus presents a plurality of binding sites for MAb""s, as does LFA-1xcex2. Experimental results have now shown that at least one anti-LFA-1xcex1 MAb (namely, S6F1) is useful for treating a patient having suppressed immune function from HIV infection in order to inhibit overproduction of LFA-1 on CD8 cells. In addition, experimental results have shown that anti-LFA-1xcex1 MAb""s are not the only MAbs useful for this purpose. In particular, an anti-LFA-1xcex1 MAb (namely, TS1/18) has shown efficacy according to the preferred treatment method. Thus, overproduction of LFA-1 on CD8 cells has been established for patients through infusing of S6F1 (which binds to four (4) distinct sites on the alpha chain) and through infusing TS1/18 (which binds to at least one specific site on the beta chain).
Thus the present invention envisions infusing a dose of at least one MAb selected from a group of MAbs that specifically bind to any LFA-1xcex1 binding site and any LFA-1xcex2 binding site.
HIV vaccine studies have shown that reducing CTL""s causes the host""s CD4 count to go up. The present invention is based on the deduction that the reason CD4 counts go down in the first place as a result of HIV infection is because among the various types of CTL""s, there must be an anti-self, anti-CD4 CTL. Thus, the maladaptive CTL synthesized by humans is the factor that transforms HIV infection into a catastrophic disease. This is confirmed by the work of Zarling et al, who found that because HIV infection does not lead to any serious disease in chimpanzees, it is the anti-self, anti-CD4 suicide cell, rather than HIV itself, that is directly responsible for the disease associated with HIV infection in humans.
The destructive role of the anti-self, anti-CD4 cytotoxic T-lymphocyte is overcome according to the teachings of the present invention through the use of monoclonal antibodies directed against one or more particular antigens on the anti-self, anti-CD4 killer cell or antigens on the lytics produced by such killer cell. Through infusion of particular monoclonal antibodies directed against such antigens, the anti-self, anti-CD4 cytotoxic T-lymphocytes or their lytics, as the case may be, are neutralized to prevent an HIV positive patient from developing AIDS or to cure the disease itself if the disease has sufficiently advanced into AIDS. In addition, use of adhesion antibodies neutralizes cells producing HIV to improve the health of infected patients.
More specifically, as noted above, one embodiment of the present invention utilizes monoclonal S6F1 mouse antibodies (S6F1 MAb) directed against an adhesion epitope of LFA-1. An infusion of S6F1 MAb elicits an immune response that is believed to remove HIV-producing CD4+ T lymphocytes from the peripheral blood of some adults with HIV disease. Lymphocyte trafficking into tissue has been eliminated based on mathematical statistics. Four individuals with early disease were treated in accordance with the present invention. HIV-producing cells were removed by antibody infusion and replaced by single marked (CD4+CD8xe2x88x92)CD4+ T lymphocytes in all four individuals. The replacement cells circulated while a decrease in serum levels of HIV RNA persisted, thereby indicating that the newly-circulating cells are uninfected. These single-marked cells are functional as evidenced by an improvement in delayed cutaneous hypersensitivity reaction.
It is thus a primary objective of the present invention to provide a method for preventing and/or curing HIV disease by eliminating or neutralizing anti-self, anti-CD4 CTL""s or their lytics from the circulating blood of an HIV-infected patient through the infusion of monoclonal antibodies directed against the antigens presented by such cells or their lytics.
These and other objects of the invention are provided in a method which transforms HIV into a nonserious infection. This is accomplished by neutralizing or removing the anti-self, anti-CD4 suicide cell from the circulating blood of an individual infected with HIV or who is at risk of such infection, and by neutralizing or removing HIV-producing cells.
The foregoing has outlined some of the more pertinent objects of the present invention. These objects should be construed to be merely illustrative of some of the more prominent features and applications of the invention. Many other beneficial results can be attained by applying the disclosed invention in a different manner or modifying the invention as will be described. Accordingly, other objects and a fuller understanding of the invention may be had by referring to the following Detailed Description of the preferred embodiment.